The osmolality of the blood in the renal inner medulla is high and varies with the urinary concentration. Both NaCl and urea are elevated. The medullary cells evidently survive and function in this adverse environment. The present studies are concerned with understanding the mechanisms involved. When cells are stressed by a high salt environment, they generally accumulate osmotically active organic solutes ("osmolytes") in order to maintain a favorable internal milieu, while regulating their volume. We identified the organic osmolytes in renal inner medullary cells as glycerophosphorylcholine (GPC), betaine, sorbitol, and inositol, and showed that the osmolyte levels varied with urine concentration (and, presumably, medullary salt concentration). We are now using renal cell cultures and living animals to study the mechanism and control of osmoregulatory accumulation of these organic osmolytes.